Abstract
BACKGROUND
Glioblastoma is associated with dismal outcomes with a survival of 15-18 months. A major challenge in glioblastoma is the inability to effectively target glioma stem cells (GSCs) that have the capacity for self-renewal. GSCs are resistant to radiation and traditional chemotherapy agents. Ibrutinib is a first-in-class, potent, small-molecule tyrosine kinase inhibitor of Bruton’s Tyrosine Kinase (BTK) and Bone marrow X-linked (BMX). BMX nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. Hence a combination of ibrutinib with radiation and temozolomide in Glioblastoma is a promising approach.
METHODS
Unmethylated MGMT GBM patients received ibrutinib daily with 60 Gy radiation over 6 weeks (Arm 1). MGMT methylated patients received Temozolomide at 75 mg/m2 in addition to Ibrutinib and radiation (Arm 2). Starting dose of Ibrutinib (level 1) was 420 mg daily, level 2 dose was 560 mg daily and dose level -1 was 280 mg. Patients received adjuvant Ibrutinib (Arm 1) and ibrutinib and temozolomide (Arm 2). The primary endpoint included the maximum tolerated dose (MTD) of Ibrutinib with radiation (Arm 1), and ibrutinib, radiation, and temozolomide (Arm 2). Progression-free survival and overall survival are secondary endpoints.
RESULTS
27 patients (15 males, 12 females), with a median age of 63 years (range, 34-77 years) were treated on two arms. Dose Limiting toxicity (DLT) in Arm 1 included grade 3 weakness, grade 4 transaminases, and grade 4 neutropenia. DLT in Arm 2 included grade 3 rash, grade 3 transaminases, grade 4 neutropenia, and thrombocytopenia. Ibrutinib was too toxic with radiation in Arm 1, MTD of 420 mg ibrutinib was confirmed in Arm 2.
CONCLUSION
MTD of Ibrutinib is 420 mg daily with Temozolomide and radiation. Efficacy outcomes (PFS and OS) will be presented.